Organelle Biogenesis and Function
Understanding formation of peroxisomes and lipid droplets (LD) is not only a fundamental cell biological problem but also has important medical implications. Several life-threatening diseases are directly associated with the function of these organelles, including neurological disorder such as Zellweger syndrome associated with peroxisome function, and lipodystrophies, diabetes and obesity with LD function.
Intracellular membrane-bound organelles are a hallmark of all eukaryotic cells. Understanding how cells generate different organelles that display characteristic morphologies remains one of the central problems in cell biology. Some organelles, like the endoplasmic reticulum (ER) and mitochondria are self-generating whereas other organelles such as peroxisomes and lipid droplets (LDs) can be generated de novo from specialized subdomains in the ER membrane. Remarkably little is known about the ER subdomains and how they regulate organelle biogenesis. Our lab utilizes multidisciplinary approaches to investigate formation and function of organelles at the ER subdomains in normal and pathological conditions.
The ER is a continuous membrane-bound organelle that extends from outer nuclear membrane to highly dynamic interconnected web of tubules in the cell periphery. The evolutionary conserved ER membrane proteins such as reticulons generate ER tubules. Reticulons and reticulon-like proteins harbor reticulon homology domain (RHD) that is proposed to bend the membrane to generate tubules. We previously discovered novel RHD containing ER shaping proteins, Pex30 and Pex30-like proteins in yeasts and multiple C2 domain containing transmembrane proteins (MCTP) in higher eukaryotes. Similar to reticulons, Pex30/MCTP generates tubules in vitro and in cells. However, unlike the reticulons, Pex30/MCTP are low abundance proteins and are enriched at specialized ER subdomains that are sites of nascent peroxisome and LD biogenesis.
Using combination of cell biological, genetic and biochemical approaches in S. cerevisiae and mammalian cells, we are currently investigating molecular mechanisms of organelle formation and function at ER subdomains.
1 ) Determining the role of MCTPs in organelle biogenesis at ER subdomains.
2) Investigating molecular mechanisms of nascent peroxisome vesicle formation from the ER membrane.
3) Identifying novel regulators of peroxisome and LD biogenesis using genome-wide approaches
Joshi Lab 